The heart is a pump comprised of muscle tissue that responds to electrical stimulation. A heartbeat is a precisely controlled event that relies on synchronization between the atrial and ventricular chambers to maximize pumping efficiency. The sinoatrial node, which is located in the right atrium of the heart, generates the electrical stimulus. In a healthy person, the sinoatrial node normally generates electrical stimulus signals at a 60-100 Hz rate, and the waves of myocardial excitation and contraction spread throughout the heart in well-defined manner. The electrical stimulus signals cause contractions in the heart's chambers, thereby pumping blood through the chambers. The left and right atria of the heart contract first and for a brief time, and then the left and right ventricles contract for a brief time. Normal heart rhythm is referred to as “sinus” rhythm, because it originates in the sinoatrial node (also referred to as the sinus node). The electrical stimulus signal output by the sinoatrial node is first sent to the left and right atria, then through the atrioventricular node and into the left and right ventricles.
An electrocardiogram (“ECG”) measures the heart's electrical activity. Electrodes are placed at specific locations on the body to capture a tracing of the heart's electrical activity. The electrical activity resulting from heart depolarization and heart repolarization is recorded by each lead. The ECG is a summation of the information recorded from each lead. The captured ECG reflects the direction of electrical current flow, and the magnitude of the muscle that is depolarized. Therefore, when the atria depolarize (and contract) the ECG tracing is smaller as compared to when the ventricles contract, since the atria are much smaller than the ventricles. Ventricle repolarization is in the same direction (positive) as ventricle depolarization. Although an ECG is positive during membrane depolarization and negative during repolarization, the direction with respect to ventricles is the same since ventricles depolarize from the inside to the outside (endocardium to epicardium), while repolarization occurs in the opposite direction.
Referring to FIG. 1, an ECG tracing is illustrated. The cardiac cycle begins with a P-wave, wherein the spontaneously firing cells in the sinoatrial node reach a threshold and generate action potentials. A wave of depolarization spreads to the left and downward though left and right atria, which is labeled in FIG. 1 as the “P wave.” The atria that were hyperpolarized suddenly become depolarized, and the ECG records a positive deflection. When the left and right atria become depolarized, the ECG returns to zero. The electrical current passes through the atrioventricular node, causing a delay of about one-tenth of a second. Due to the small mass of the atrioventricular node, the ECG tracing does not record any electrical activity. When the atrioventricular node is depolarized, it triggers depolarization of the Purkinje fibers. The Purkinje fibers spread the electrical current throughout the left and right ventricles, thereby causing depolarization across each ventricle simultaneously. Since the tissue mass of the Purkinje fibers is small, the ECG tracing does not record any electrical activity. The passing of the electrical current through the atrioventricular node and the Purkinje fibers is labeled in FIG. 1 as the “PR segment.”
The depolarization of the left and right ventricles is referred to as the “QRS complex,” and FIG. 1 is labeled as such. The QRS complex is quite large since the left and right ventricle tissue is large in comparison to the sinoatrial node. The three peaks are indicative of the manner in which the electrical current spreads through the left and right ventricles (i.e., from inside to outside) and indicative of the fact that the tissue mass of the left ventricle is greater than the tissue mass of the right ventricle. The complete depolarization of the left and right ventricles indicates that the QRS complex has terminated.
Referring to FIG. 2, the points of the QRS complex are labeled. As noted above, the QRS complex is indicative of the depolarization of the left and right ventricles. The ventricular depolarization begins at a left side of the intraventricular septum, and the peak of this depolarization is shown by the “Q” peak of the QRS complex. The ventricular depolarization spreads from the endocardial surface of the left ventricle to the epicardial surface of the left ventricle, and is shown by the “R” peak of the QRS complex. The spread of the ventricular depolarization to the right ventricle is shown by the “S” peak of the QRS complex.
The segment labeled “T wave” in FIG. 1 indicates repolarization of the left and right ventricles. Although the left and right ventricles are repolarizing, the T wave is positive, since the heart repolarizes from outside to inside, which is the opposite direction of depolarization (inside to outside). The completion of the T wave signals marks the end of the cardiac cycle.
Referring to FIG. 3, the captured tracing of electrical activity is printed out on a paper tape or is presented on a display. Anomalies in an ECG waveform are indicative of various heart-related conditions, such as ischemia, myocardial infarction, conduction disorder, electrolyte disturbance, pericarditis, valve disease or enlarged heart. Certain arrhythmias might occur only on an intermittent basis, or only if certain psychological or physical factors (i.e., stress, fatigue, etc.) are present. Since a typical ECG tracing is only a few minutes in length, arrhythmias of this type are difficult to capture. A more lengthy ECG tracing, referred to as a Holter monitor, is used to capture any arrhythmias or other abnormal activity. The Holter monitor may record a heart's activity over a period of several days.
Referring to FIG. 1, one of the segments that is measured is the referred to as the QT interval, and the QT interval indicates the duration of the electrical activity that controls contraction of the cells of the heart muscle. The QT interval represents the duration of ventricular depolarization and subsequent repolarization, beginning at the initiation of the Q wave of the QRS complex and ending where the T wave returns to the isoelectric baseline. QT interval prolongation creates an electrophysiological environment that favors the development of cardiac arrhythmias, most commonly torsade de pointes, but possibly other ventricular arrhythmias as well. Long QT syndrome identifies a condition wherein there exists an abnormally long QT interval on the ECG tracing. The term “congenital long QT” refers to a long QT interval that is inherited. The inherited form occurs due to irregularities in particular heart cell proteins, and, of course, these protein irregularities are caused by abnormalities in the genes that produce those proteins. The term “acquired long QT” refers to a long QT interval that is brought about by drugs or anomalous levels of the salts within blood (e.g., potassium and magnesium).
Although a person might have an unremarkable QT interval under normal conditions, that person might develop a prolonged QT or suffer torsades de pointes (“TdP”) when taking certain medications. As shown in FIG. 4, TdP refers to the characteristic appearance of the electrocardiogram indicative of a rhythm abnormality, and typically occurs in the setting of a prolonged QT interval on the electrocardiogram. TdP is a polymorphic ventricular tachyarrhythmia that manifests on the ECG tracing as continuous twisting of the vector of the QRS complex around the isoelectric baseline. A feature of TdP is pronounced prolongation of the QT interval in the sinus beats preceding the arrhythmia. TdP can degenerate into life-threatening cardiac rhythms that can result in blackouts or sudden death. Measurement of the QT interval on the ECG tracing is still the main method of determining whether a person has long QT interval syndrome, whether inherited or acquired.
Non-antiarrhythmic drugs can have an undesirable side effect of causing delayed cardiac repolarization. Due to its relationship to heart rate, the QT interval is normalized into a heart rate independent “corrected” value known as the QTc interval, which represents the QT interval at a standardized heart rate (essentially the QT interval at a heart rate of 60 bpm). Several drugs that have caused TdP clearly increase both the absolute QT interval and the QTc interval.